Importance of a syndapin-mediated interconnection of cytoskeleton and membrane trafficking for neuronal structure, function and plasticity

突触后可塑性机制被认为是学习和记忆的结构基础。为了满足大脑的生长、适应和可塑性的要求，动态适应是必不可少的，动态适应反映在对不同刺激的突触接触的数量、形态和重组的变化中。在分子水平上，突触后特化中的这些过程的特征是AMPA型谷氨酸受体的质膜水平的调节和肌动蛋白细胞骨架的动态。包括突触的形成、成熟和可塑性重构的结构重组与通过调节受体内吞作用和通过这些过程的分子连接再循环来调节可活化AMPA受体比例的协调为活性依赖性突触修饰提供了有吸引力的统一机制。我们以前在非神经元细胞中的分析已经证明，syndapins在肌动蛋白细胞骨架动力学，受体介导的内吞作用和膜受体的内体再循环中发挥重要作用，并进一步确保这些不同的细胞功能之间的功能互连。我们已经建立的主要神经元syndapin I亚型的诱导型敲除小鼠的形态和功能表征将揭示这种协调蛋白在突触后形态的结构组织和动力学以及受体膜运输过程中的作用。在整个动物水平上，在功能性脑切片和原代细胞培养系统中，本项目过程中的分析将揭示syndapin I介导的肌动蛋白动力学、突触后密度的特化细胞基质组分、受体介导的内吞作用和内体受体再循环的相互联系如何超越对形成、成熟、保存、突触后神经末梢的功能和可塑性调节，因此是神经元可塑性的基础。

Postsynaptic plasticity mechanisms are considered to be the structural basis of learning and memory. To meet the requirements of growth, adaptation and plasticity of the brain, dynamic adaptations reflected in changes in number, morphology and reorganization of synaptic contacts in response to diverse stimuli are indispensable. At the molecular level, these processes in postsynaptic specializations are characterized by the modulation of the plasma membrane levels of AMPA-type glutamate receptors and by dynamics of the actin cytoskeleton. A coordination of structural reorganizations including formation, maturation and plastic restructuring of synapses with a modulation of the activatable AMPA-receptor proportion through regulation of receptor endocytosis and recycling by molecular links of these processes provides an attractive unifying mechanism for activity-dependent synapse modification. Our previous analyses in non-neuronal cells have demonstrated that syndapins play an essential role in actin cytoskeletal dynamics, receptor-mediated endocytosis and endosomal recycling of membrane receptors and furthermore ensure functional interconnections between these different cellular functions. The morphological and functional characterization of the inducible knockout mice of the mainly neuronal syndapin I isoform that we have established shall unravel the role of this coordinator protein in the structural organization and dynamics of postsynaptic morphology as well as in receptor membrane trafficking processes. Analyses in the course of this project at the whole animal level, in functional brain sections and in primary cell culture systems shall reveal how syndapin I-mediated interconnections of actin dynamics, specialized cytomatrix components of the postsynaptic density, receptor-mediated endocytosis and endosomal receptor recycling overtake coordinative functions that are crucial for the formation, maturation, preservation, function and plastic modulation of postsynaptic nerve endings and thus underlie neuronal plasticity.